Delivery of nonsteroidal antiinflammatory drugs through an inhalation route

ABSTRACT

The present invention relates to the delivery of nonsteroidal antiinflammatory drugs (NSAIDs) through an inhalation route. Specifically, it relates to aerosols containing NSAIDs that are used in inhalation therapy. In a method aspect of the present invention, an NSAID is delivered to a patient through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises an NSAID, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles with less than 5% NSAID degradation products. In a kit aspect of the present invention, a kit for delivering an NSAID through an inhalation route is provided which comprises: a) a thin coating of an NSAID composition and b) a device for dispensing said thin coating as a condensation aerosol.

This application is a continuation of U.S. patent application Ser. No.10/155,097, entitled “Delivery of Nonsteroidal Antiinflammatory DrugsThrough an Inhalation Route,” filed May 23, 2002 now U.S. Pat. No.6,716,417, Rabinowitz and Zaffaroni, which claims priority to U.S.provisional application Ser. No. 60/294,203 entitled “Thermal VaporDelivery of Drugs,” filed May 24, 2001, Rabinowitz and Zaffaroni and toU.S. provisional application Ser. No. 60/317,479 entitled “Aerosol DrugDelivery,” filed Sep. 5, 2001, Rabinowitz and Zaffaroni, the entiredisclosures of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to the delivery of nonsteroidalanti-inflammatory drugs (NSAIDs) through an inhalation route.Specifically, it relates to aerosols containing NSAIDs that are used ininhalation therapy.

BACKGROUND OF THE INVENTION

There are a number of nonsteroidal compositions currently marketed forthe treatment of inflammation. The compositions contain at least oneactive ingredient that provides for observed therapeutic effects. Amongthe active ingredients given in such antiinflammatory compositions areindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, and nabumetone.

It is desirable to provide a new route of administration fornonsteroidal antiinflammatory drugs that rapidly produces peak plasmaconcentrations of the compounds. The provision of such a route is anobject of the present invention.

SUMMARY OF THE INVENTION

The present invention relates to the delivery of nonsteroidalanti-inflammatory drugs (NSAIDs) through an inhalation route.Specifically, it relates to aerosols containing NSAIDs that are used ininhalation therapy.

In a composition aspect of the present invention, the aerosol comprisesparticles comprising at least 5 percent by weight of an NSAID.Preferably, the particles comprise at least 10 percent by weight of anNSAID. More preferably, the particles comprise at least 20 percent, 30percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97percent by weight of an NSAID.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofNSAID degradation products. Preferably, the particles comprise less than5 percent by weight of NSAID degradation products. More preferably, theparticles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weightof NSAID degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the aerosol has an inhalable aerosol particle density greaterthan 10⁶ particles/mL. Preferably, the aerosol has an inhalable aerosolparticle density greater than 10⁷ particles/mL or 10⁸ particles/mL.

Typically, the aerosol particles have a mass median aerodynamic diameterof less than 5 microns. Preferably, the particles have a mass medianaerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.5.Preferably, the geometric standard deviation is less than 3.0. Morepreferably, the geometric standard deviation is less than 2.5 or 2.2.

Typically, the aerosol is formed by heating a composition containing anNSAID to form a vapor and subsequently allowing the vapor to condenseinto an aerosol.

In another composition aspect of the present invention, the aerosolcomprises particles comprising at least 5 percent by weight ofindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone. Preferably, the particles comprise at least10 percent by weight of indomethacin, ketoprofen, celcoxib, rofecoxib,meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen,ibuprofen, flurbiprofen, or nabumetone. More preferably, the particlescomprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent or 99.97 percent by weight of indomethacin,ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen,diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen, ornabumetone.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone degradation products. Preferably, theparticles comprise less than 5 percent by weight of indomethacin,ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen,diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen, ornabumetone degradation products. More preferably, the particles compriseless than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of indomethacin,ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen,diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen, ornabumetone degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the aerosol has an inhalable aerosol drug mass densitygreater than 5 mg/L. Preferably, the aerosol has an inhalable aerosoldrug mass density greater than 7.5 mg/L. More preferably, the aerosolhas an inhalable aerosol drug mass density greater than 10 mg/L.

Typically, the aerosol has an inhalable aerosol particle density greaterthan 10⁶ particles/mL. Preferably, the aerosol has an inhalable aerosolparticle density greater than 10⁷ particles/mL or 10⁸ particles/mL.

Typically, the aerosol particles have a mass median aerodynamic diameterof less than 5 microns. Preferably, the particles have a mass medianaerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.5.Preferably, the geometric standard deviation is less than 3.0. Morepreferably, the geometric standard deviation is less than 2.5 or 2.2.

Typically, the aerosol is formed by heating a composition containingindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone to form a vapor and subsequently allowingthe vapor to condense into an aerosol.

In a method aspect of the present invention, an NSAID is delivered to amammal through an inhalation route. The method comprises: a) heating acomposition, wherein the composition comprises at least 5 percent byweight of an NSAID, to form a vapor; and, b) allowing the vapor to cool,thereby forming a condensation aerosol comprising particles, which isinhaled by the mammal. Preferably, the composition that is heatedcomprises at least 10 percent by weight of an NSAID. More preferably,the composition comprises at least 20 percent, 30 percent, 40 percent,50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent,97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of an NSAID.

Typically, the particles comprise at least 5 percent by weight of anNSAID. Preferably, the particles comprise at least 10 percent by weightof an NSAID. More preferably, the particles comprise at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent,99.9 percent or 99.97 percent by weight of an NSAID.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofNSAID degradation products. Preferably, the particles comprise less than5 percent by weight of NSAID degradation products. More preferably, theparticles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of NSAIDdegradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the particles of the delivered condensation aerosol have amass median aerodynamic diameter of less than 5 microns. Preferably, theparticles have a mass median aerodynamic diameter of less than 3microns. More preferably, the particles have a mass median aerodynamicdiameter of less than 2 or 1 micron(s). In certain embodiments theparticles have an MMAD of from about 0.2 to about 3 microns.

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.5.Preferably, the geometric standard deviation is less than 3.0. Morepreferably, the geometric standard deviation is less than 2.5 or 2.2.

Typically, the delivered aerosol has an inhalable aerosol particledensity greater than 10⁶ particles/mL. Preferably, the aerosol has aninhalable aerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

Typically, the rate of inhalable aerosol particle formation of thedelivered condensation aerosol is greater than 10⁸ particles per second.Preferably, the aerosol is formed at a rate greater than 10⁹ inhalableparticles per second. More preferably, the aerosol is formed at a rategreater than 10¹⁰ inhalable particles per second.

Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, the delivered condensation aerosol results in a peak plasmaconcentration of an NSAID in the mammal in less than 1 h. Preferably,the peak plasma concentration is reached in less than 0.5 h. Morepreferably, the peak plasma concentration is reached in less than 0.2,0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

In another method aspect of the present invention, one of indomethacin,ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen,diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen, ornabumetone is delivered to a mammal through an inhalation route. Themethod comprises: a) heating a composition, wherein the compositioncomprises at least 5 percent by weight of indomethacin, ketoprofen,celcoxib, rofecoxib, meclofenamic acid, fenoprofen, diflunisal,tolfenamic acid, naproxen, ibuprofen, flurbiprofen, or nabumetone, toform a vapor; and, b) allowing the vapor to cool, thereby forming acondensation aerosol comprising particles, which is inhaled by themammal. Preferably, the composition that is heated comprises at least 10percent by weight of indomethacin, ketoprofen, celcoxib, rofecoxib,meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen,ibuprofen, flurbiprofen, or nabumetone. More preferably, the compositioncomprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent, 99.9 percent or 99.97 percent by weight ofindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone.

Typically, the particles comprise at least 5 percent by weight ofindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone. Preferably, the particles comprise at least10 percent by weight of indomethacin, ketoprofen, celcoxib, rofecoxib,meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen,ibuprofen, flurbiprofen, or nabumetone. More preferably, the particlescomprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent, 99.9 percent or 99.97 percent by weight ofindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone degradation products. Preferably, theparticles comprise less than 5 percent by weight of indomethacin,ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen,diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen, ornabumetone degradation products. More preferably, the particles comprise2.5, 1, 0.5, 0.1 or 0.03 percent by weight of indomethacin, ketoprofen,celcoxib, rofecoxib, meclofenamic acid, fenoprofen, diflunisal,tolfenamic acid, naproxen, ibuprofen, flurbiprofen, or nabumetonedegradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the particles of the delivered condensation aerosol have amass median aerodynamic diameter of less than 5 microns. Preferably, theparticles have a mass median aerodynamic diameter of less than 3microns. More preferably, the particles have a mass median aerodynamicdiameter of less than 2 or 1 micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.5.Preferably, the geometric standard deviation is less than 3.0. Morepreferably, the geometric standard deviation is less than 2.5 or 2.2.

Typically, the delivered aerosol has an inhalable aerosol drug massdensity greater than 5 mg/L. Preferably, the delivered aerosol has aninhalable aerosol drug mass density greater than 7.5 mg/L. Morepreferably, the delivered aerosol has an inhalable aerosol drug massdensity greater than 10 mg/L.

Typically, the delivered aerosol has an inhalable aerosol particledensity greater than 10⁶ particles/mL. Preferably, the aerosol has aninhalable aerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

Typically, the rate of inhalable aerosol particle formation of thedelivered condensation aerosol is greater than 10⁸ particles per second.Preferably, the aerosol is formed at a rate greater than 10⁹ inhalableparticles per second. More preferably, the aerosol is formed at a rategreater than 10¹⁰ inhalable particles per second.

Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, greater than 5 mg of indomethacin, ketoprofen, celcoxib,rofecoxib, meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid,naproxen, ibuprofen, flurbiprofen, or nabumetone is delivered to themammal in a single inspiration. Preferably, greater than 7.5 mg ofindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone is delivered to the mammal in a singleinspiration. More preferably, greater than 10 mg of indomethacin,ketoprofen, celcoxib, rofecoxib, meclofenamic acid, fenoprofen,diflunisal, tolfenamic acid, naproxen, ibuprofen, flurbiprofen, ornabumetone is delivered to the mammal in a single inspiration.

Typically, the delivered condensation aerosol results in a peak plasmaconcentration of indomethacin, ketoprofen, celcoxib, rofecoxib,meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen,ibuprofen, flurbiprofen, or nabumetone in the mammal in less than 1 h.Preferably, the peak plasma concentration is reached in less than 0.5 h.More preferably, the peak plasma concentration is reached in less than0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

In a kit aspect of the present invention, a kit for delivering an NSAIDthrough an inhalation route to a mammal is provided which comprises: a)a composition comprising at least 5 percent by weight of an NSAID; and,b) a device that forms an NSAID drug aerosol from the composition, forinhalation by the mammal. Preferably, the composition comprises at least20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent,80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5percent, 99.9 percent or 99.97 percent by weight of an NSAID.

Typically, the device contained in the kit comprises: a) an element forheating the NSAID composition to form a vapor; b) an element allowingthe vapor to cool to form an aerosol; and, c) an element permitting themammal to inhale the aerosol.

In a kit aspect of the present invention, a kit for deliveringindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone through an inhalation route to a mammal isprovided which comprises: a) a composition comprising at least 5 percentby weight of indomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamicacid, fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone; and, b) a device that forms anindomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamic acid,fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone aerosol from the composition, for inhalationby the mammal. Preferably, the composition comprises at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent,99.9 percent or 99.97 percent by weight of indomethacin, ketoprofen,celcoxib, rofecoxib, meclofenamic acid, fenoprofen, diflunisal,tolfenamic acid, naproxen, ibuprofen, flurbiprofen, or nabumetone.

Typically, the device contained in the kit comprises: a) an element forheating the indomethacin, ketoprofen, celcoxib, rofecoxib, meclofenamicacid, fenoprofen, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, or nabumetone composition to form a vapor; b) an elementallowing the vapor to cool to form an aerosol; and, c) an elementpermitting the mammal to inhale the aerosol.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows a cross-sectional view of a device used to deliver NSAIDaerosols to a mammal through an inhalation route.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

“Aerodynamic diameter” of a given particle refers to the diameter of aspherical droplet with a density of 1 g/mL (the density of water) thathas the same settling velocity as the given particle.

“Aerosol” refers to a suspension of solid or liquid particles in a gas.

“Aerosol drug mass density” refers to the mass of NSAID per unit volumeof aerosol.

“Aerosol mass density” refers to the mass of particulate matter per unitvolume of aerosol.

“Aerosol particle density” refers to the number of particles per unitvolume of aerosol.

“Amorphous particle” refers to a particle that does not contain morethan 50 percent by weight of a crystalline form. Preferably, theparticle does not contain more than 25 percent by weight of acrystalline form. More preferably, the particle does not contain morethan 10 percent by weight of a crystalline form.

“Celecoxib” refers to4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.

“Celecoxib degradation product” refers to a compound resulting from achemical modification of celecoxib. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Condensation aerosol” refers to an aerosol formed by vaporization of asubstance followed by condensation of the substance into an aerosol.

“Diflunisal” refers to2′,4′-difluoro-4-hydroxy-[1,1′-biphenyl]-3-carboxylic acid.

“Diflunisal degradation product” refers to a compound resulting from achemical modification of diflunisal. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Fenoprofen” refers to α-methyl-3-phenoxy-benzeneacetic acid.

“Fenoprofen degradation product” refers to a compound resulting from achemical modification of fenoprofen. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Flurbiprofen” refers to 2-fluoro-α-methyl-[1,1′-biphenyl]-4-aceticacid.

“Flurbiprofen degradation product” refers to a compound resulting from achemical modification of flurbiprofen. The modification, for example,can be the result of a thermally or photochemically induced reaction.Such reactions include, without limitation, oxidation and hydrolysis.

“Ibuprofen” refers to α-methyl-4-(2-methyl-propyl)benzene acetic acid.

“Ibuprofen degradation product” refers to a compound resulting from achemical modification of ibuprofen. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Indomethacin” refers to1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid.

“Indomethacin degradation product” refers to a compound resulting from achemical modification of indomethacin. The modification, for example,can be the result of a thermally or photochemically induced reaction.Such reactions include, without limitation, oxidation and hydrolysis.

“Inhalable aerosol drug mass density” refers to the aerosol drug massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

“Inhalable aerosol mass density” refers to the aerosol mass densityproduced by an inhalation device and delivered into a typical patienttidal volume.

“Inhalable aerosol particle density” refers to the aerosol particledensity of particles of size between 100 nm and 5 microns produced by aninhalation device and delivered into a typical patient tidal volume.

“Ketoprofen” refers to 3-benzoyl-α-methyl-benzeneacetic acid.

“Ketoprofen degradation product” refers to a compound resulting from achemical modification of ketoprofen. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Mass median aerodynamic diameter” or “MMAD” of an aerosol refers to theaerodynamic diameter for which half the particulate mass of the aerosolis contributed by particles with an aerodynamic diameter larger than theMMAD and half by particles with an aerodynamic diameter smaller than theMMAD.

“Meclofenamic Acid” refers to2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid.

“Meclofenamic acid degradation product” refers to a compound resultingfrom a chemical modification of meclofenamic acid. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

“Nabumetone” refers to 4-(6-methoxy-2-naphthalenyl)-2-butanone.

“Nabumetone degradation product” refers to a compound resulting from achemical modification of nabumetone. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Naproxen” refers to (αS)-6-methoxy-α-methyl-2-naphthaleneacetic acid.

“Naproxen degradation product” refers to a compound resulting from achemical modification of naproxen. The modification, for example, can bethe result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“NSAID degradation product” refers to a compound resulting from achemical modification of an NSAID. The modification, for example, can bethe result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

“Rate of inhalable aerosol particle formation” refers to the number ofparticles of size between 100 nm and 5 microns produced by an inhalationdevice per unit time.

“Rate of drug aerosol formation” refers to the mass of aerosolized NSAIDproduced by an inhalation device per unit time.

“Rofecoxib” refers to4-[4-(methylsulfonyl)-phenyl]-3-phenyl-2(5H)-furanone.

“Rofecoxib degradation product” refers to a compound resulting from achemical modification of rofecoxib. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Tolfenamic acid” refers to 2-[(3-chloro-2-methylphenyl)amino]benzoicacid.

“Tolfenamic acid degradation product” refers to a compound resultingfrom a chemical modification of tolfenamic acid. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

“Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

“Typical patient tidal volume” refers to 1 L for an adult patient and 15mL/kg for a pediatric patient.

“Vapor” refers to a gas, and “vapor phase” refers to a gas phase. Theterm “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

Formation of NSAID Containing Aerosols

Any suitable method is used to form the aerosols of the presentinvention. A preferred method, however, involves heating a compositioncomprising an NSAID to form a vapor, followed by cooling of the vaporsuch that it condenses to provide an NSAID comprising aerosol(condensation aerosol). The composition is heated in one of four forms:as pure active compound (e.g., pure indomethacin, ketoprofen, celcoxib,rofecoxib, meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid,naproxen, ibuprofen, flurbiprofen, or nabumetone); as a mixture ofactive compound and a pharmaceutically acceptable excipient; as a saltform of the pure active compound; and, as a mixture of active compoundsalt form and a pharmaceutically acceptable excipient.

Salt forms of NSAIDs (e.g., indomethacin, ketoprofen, celcoxib,rofecoxib, meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid,naproxen, ibuprofen, flurbiprofen, or nabumetone) are eithercommercially available or are obtained from the corresponding free baseusing well known methods in the art. A variety of pharmaceuticallyacceptable salts are suitable for aerosolization. Such salts include,without limitation, the following: hydrochloric acid, hydrobromic acid,acetic acid, maleic acid, formic acid, and fumaric acid salts.

Pharmaceutically acceptable excipients may be volatile or nonvolatile.Volatile excipients, when heated, are concurrently volatilized,aerosolized and inhaled with the NSAID. Classes of such excipients areknown in the art and include, without limitation, gaseous, supercriticalfluid, liquid and solid solvents. The following is a list of exemplarycarriers within the classes: water; terpenes, such as menthol; alcohols,such as ethanol, propylene glycol, glycerol and other similar alcohols;dimethylformamide; dimethylacetamide; wax; supercritical carbon dioxide;dry ice; and mixtures thereof.

Solid supports on which the composition is heated are of a variety ofshapes. Examples of such shapes include, without limitation, cylindersof less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness andvirtually any shape permeated by small (e.g., less than 1.0 mm-sized)pores. Preferably, solid supports provide a large surface to volumeratio (e.g., greater than 100 per meter) and a large surface to massratio (e.g., greater than 1 cm² per gram).

A solid support of one shape can also be transformed into another shapewith different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

A number of different materials are used to construct the solidsupports. Classes of such materials include, without limitation, metals,inorganic materials, carbonaceous materials and polymers. The followingare examples of the material classes: aluminum, silver, gold, stainlesssteel, copper and tungsten; silica, glass, silicon and alumina;graphite, porous carbons, carbon yarns and carbon felts;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

Where aluminum is used as a solid support, aluminum foil is a suitablematerial. Examples of silica, alumina and silicon based materialsinclude amphorous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (analumina of defined surface area greater than 2 m²/g from Aldrich, St.Louis, Mo.) and a silicon wafer as used in the semiconductor industry.Carbon yarns and felts are available from American Kynol, Inc., NewYork, N.Y. Chromatography resins such as octadecycl silane chemicallybonded to porous silica are exemplary coated variants of silica.

The heating of the NSAID compositions is performed using any suitablemethod. Examples of methods by which heat can be generated include thefollowing: passage of current through an electrical resistance element;absorption of electromagnetic radiation, such as microwave or laserlight; and, exothermic chemical reactions, such as exothermic solvation,hydration of pyrophoric materials and oxidation of combustiblematerials.

Delivery of NSAID Containing Aerosols

NSAID containing aerosols of the present invention are delivered to amammal using an inhalation device. Where the aerosol is a condensationaerosol, the device has at least three elements: an element for heatingan NSAID containing composition to form a vapor; an element allowing thevapor to cool, thereby providing a condensation aerosol; and, an elementpermitting the mammal to inhale the aerosol. Various suitable heatingmethods are described above. The element that allows cooling is, in itsimplest form, an inert passageway linking the heating means to theinhalation means. The element permitting inhalation is an aerosol exitportal that forms a connection between the cooling element and themammal's respiratory system.

One device used to deliver the NSAID containing aerosol is described inreference to FIG. 1. Delivery device 100 has a proximal end 102 and adistal end 104, a heating module 106, a power source 108, and amouthpiece 110. An NSAID composition is deposited on a surface 112 ofheating module 106. Upon activation of a user activated switch 114,power source 108 initiates heating of heating module 106 (e.g, throughignition of combustible fuel or passage of current through a resistiveheating element). The NSAID composition volatilizes due to the heatingof heating module 106 and condenses to form a condensation aerosol priorto reaching the mouthpiece 110 at the proximal end of the device 102.Air flow traveling from the device distal end 104 to the mouthpiece 110carries the condensation aerosol to the mouthpiece 110, where it isinhaled by the mammal.

Devices, if desired, contain a variety of components to facilitate thedelivery of NSAID containing aerosols. For instance, the device mayinclude any component known in the art to control the timing of drugaerosolization relative to inhalation (e.g., breath-actuation), toprovide feedback to patients on the rate and/or volume of inhalation, toprevent excessive use (i.e., “lock-out” feature), to prevent use byunauthorized individuals, and/or to record dosing histories.

Dosage of NSAID Containing Aerosols

The dosage amount of an NSAID in aerosol form is generally no greaterthan twice the standard dose of the drug given orally; oftentimes, thedose is less than the standard oral dose. (Indomethacin, ketoprofen,celcoxib, rofecoxib, meclofenamic acid, fenoprofen, diflunisal,tolfenamic acid, naproxen, ibuprofen, flurbiprofen, or nabumetone aretypically provided at the following strengths for oral administration:25 mg, 25 to 50 mg, 100 mg, 50 mg, 200 mg, 50 mg, 200 mg, 250 mg, 200mg, 250 mg, 200 mg, 50 mg, and 500 mg respectively.) A typical dosage ofan NSAID aerosol is either administered as a single inhalation or as aseries of inhalations taken within an hour or less (dosage equals sum ofinhaled amounts). Where the drug is administered as a series ofinhalations, a different amount may be delivered in each inhalation.

One can determine the appropriate dose of NSAID containing aerosols totreat a particular condition using methods such as animal experimentsand a dose-finding (Phase I/II) clinical trial. One animal experimentinvolves measuring plasma concentrations of drug in an animal after itsexposure to the aerosol. Mammals such as dogs or primates are typicallyused in such studies, since their respiratory systems are similar tothat of a human. Initial dose levels for testing in humans is generallyless than or equal to the dose in the mammal model that resulted inplasma drug levels associated with a therapeutic effect in humans. Doseescalation in humans is then performed, until either an optimaltherapeutic response is obtained or a dose-limiting toxicity isencountered.

Analysis of NSAID Containing Aerosols

Purity of an NSAID containing aerosol is determined using a number ofmethods, examples of which are described in Sekine et al., Journal ofForensic Science 32:1271–1280 (1987) and Martin et al., Journal ofAnalytic Toxicology 13:158–162 (1989). One method involves forming theaerosol in a device through which a gas flow (e.g., air flow) ismaintained, generally at a rate between 0.4 and 60 L/min. The gas flowcarries the aerosol into one or more traps. After isolation from thetrap, the aerosol is subjected to an analytical technique, such as gasor liquid chromatography, that permits a determination of compositionpurity.

A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

The gas or liquid chromatograph discussed above contains a detectionsystem (i.e., detector). Such detection systems are well known in theart and include, for example, flame ionization, photon absorption andmass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure of NSAIDdegradation products.

Particle size distribution of an NSAID containing aerosol is determinedusing any suitable method in the art (e.g., cascade impaction). AnAndersen Eight Stage Non-viable Cascade Impactor (Andersen Instruments,Smyrna, Ga.) linked to a furnace tube by a mock throat (USP throat,Andersen Instruments, Smyrna, Ga.) is one system used for cascadeimpaction studies.

Inhalable aerosol mass density is determined, for example, by deliveringa drug-containing aerosol into a confined chamber via an inhalationdevice and measuring the mass collected in the chamber. Typically, theaerosol is drawn into the chamber by having a pressure gradient betweenthe device and the chamber, wherein the chamber is at lower pressurethan the device. The volume of the chamber should approximate the tidalvolume of an inhaling patient.

Inhalable aerosol drug mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the tidal volume of an inhalingpatient. The amount of active drug compound collected in the chamber isdetermined by extracting the chamber, conducting chromatographicanalysis of the extract and comparing the results of the chromatographicanalysis to those of a standard containing known amounts of drug.

Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice and measuring the number of particles of given size collected inthe chamber. The number of particles of a given size may be directlymeasured based on the light-scattering properties of the particles.Alternatively, the number of particles of a given size is determined bymeasuring the mass of particles within the given size range andcalculating the number of particles based on the mass as follows: Totalnumber of particles=Sum (from size range 1 to size range N) of number ofparticles in each size range. Number of particles in a given sizerange=Mass in the size range/Mass of a typical particle in the sizerange. Mass of a typical particle in a given size range=π*D³*φ/6, whereD is a typical particle diameter in the size range (generally, the meanboundary MMADs defining the size range) in microns, φ is the particledensity (in g/mL) and mass is given in units of picograms (g⁻¹²).

Rate of inhalable aerosol particle formation is determined, for example,by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 100 nm to 5 micron particles collected divided by theduration of the collection time.

Rate of aerosol formation is determined, for example, by deliveringaerosol phase drug into a confined chamber via an inhalation device. Thedelivery is for a set period of time (e.g., 3 s), and the mass ofparticulate matter collected is determined by weighing the confinedchamber before and after the delivery of the particulate matter. Therate of aerosol formation is equal to the increase in mass in thechamber divided by the duration of the collection time. Alternatively,where a change in mass of the delivery device or component thereof canonly occur through release of the aerosol phase particulate matter, themass of particulate matter may be equated with the mass lost from thedevice or component during the delivery of the aerosol. In this case,the rate of aerosol formation is equal to the decrease in mass of thedevice or component during the delivery event divided by the duration ofthe delivery event.

Rate of drug aerosol formation is determined, for example, by deliveringan NSAID containing aerosol into a confined chamber via an inhalationdevice over a set period of time (e.g., 3 s). Where the aerosol is pureNSAID, the amount of drug collected in the chamber is measured asdescribed above. The rate of drug aerosol formation is equal to theamount of NSAID collected in the chamber divided by the duration of thecollection time. Where the NSAID containing aerosol comprises apharmaceutically acceptable excipient, multiplying the rate of aerosolformation by the percentage of NSAID in the aerosol provides the rate ofdrug aerosol formation.

Utility of NSAID Containing Aerosols

The NSAID containing aerosols of the present invention are typicallyused for the treatment of inflammation.

The following examples are meant to illustrate, rather than limit, thepresent invention.

Indomethacin, ketoprofen, meclofenamic acid sodium salt, fenoprofencalcium salt, diflunisal, tolfenamic acid, naproxen, ibuprofen,flurbiprofen, and nabumetone are commercially available from SIGMA(www.sigma-aldrich.com). Celecoxib and rofecoxib can be isolated usingstandard methods from CELEBREX® and VIOXX® respectively. Other NSAIDscan be similarly obtained.

EXAMPLE 1 General Procedure for Volatilizing Compounds

A solution of drug in a minimal amount of an appropriate solvent (e.g.,dichloromethane or methanol) is coated on a 4.0 cm×7.5 cm piece ofaluminum foil (precleaned with acetone). The solvent is allowed toevaporate. The coated foil is wrapped around a 300 watt halogen tube(Feit Electric Company, Pico Rivera, Calif.), which is inserted into aglass tube sealed at one end with a rubber stopper. Running 60 V ofalternating current (driven by line power controlled by a variac)through the bulb for 3–18 s affords thermal vapor (including aerosol),which is collected on the glass tube walls. Reverse-phase HPLC analysiswith detection by absorption of 225 nm light is used to determine thepurity of the aerosol. (When desired, the system is flushed through withargon prior to volatilization.)

NSAID aerosols were obtained in the following purities and amounts usingthis procedure: indomethacin (99% purity, 0.61 mg); ketoprofen (100%purity, 2.72 mg); celecoxib (100% purity, 10 mg); rofecoxib (97.5%purity, 4.1 mg); meclofenamic acid (100% purity); fenoprofen (100%, 1.61mg); diflunisal (100%, 5.47 mg); tolfenamic acid (94.2% purity, 6.49mg); naproxen (100% purity, 4 mg); ibuprofen (100% purity, 1.81 mg);flurbiprofen (100% purity, 4.1 mg); and, nabumetone (100% purity, 4.8mg).

1. A method of treating inflammation in a patient comprisingadministering a therapeutic amount of a drug condensation aerosol to thepatient by inhalation, wherein the drug is selected from the groupconsisting of indomethacin, ketoprofen, celcoxib, rofecoxib,meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen,ibuprofen, flurbiprofen and nabumetone, and wherein the condensationaerosol is formed by heating a thin layer containing the drug, on asolid support, to produce a vapor of the drug, and condensing the vaporto form a condensation aerosol characterized by less than 10% drugdegradation products by weight, and an MMAD of less than 5 microns. 2.The method according to claim 1, wherein the condensation aerosol ischaracterized by an MMAD of less than 3 microns.
 3. The method accordingto claim 1, wherein peak plasma drug concentration is reached in lessthan 0.1 hours.
 4. The method according to claim 1, wherein thecondensation aerosol is formed at a rate greater than 0.5 mg/second. 5.The method according to claim 1, wherein at least 50% by weight of thecondensation aerosol is amorphous in form.
 6. The method according toclaim 1, wherein the therapeutic amount of a drug condensation aerosolcomprises greater than 5 mg of the drug delivered in a singleinspiration.
 7. The method according to claim 1, wherein the therapeuticamount of a drug condensation aerosol comprises greater than 7.5 mg ofthe drug delivered in a single inspiration.
 8. The method according toclaim 1, wherein the therapeutic amount of a drug condensation aerosolcomprises greater than 10 mg of the drug delivered in a singleinspiration.
 9. A method of administering a drug condensation aerosol toa patient comprising administering the drug condensation aerosol to thepatient by inhalation, wherein the drug is selected from the groupconsisting of indomethacin, ketoprofen, celcoxib, rofecoxib,meclofenamic acid, fenoprofen, diflunisal, tolfenamic acid, naproxen,ibuprofen, flurbiprofen and nabumetone, and wherein the drugcondensation aerosol is formed by heating a thin layer containing thedrug, on a solid support, to produce a vapor of the drug, and condensingthe vapor to form a condensation aerosol characterized by less than 10%drug degradation products by weight, and an MMAD of less than 5 microns.10. A kit for delivering a drug condensation aerosol comprising: a. athin layer containing the drug, on a solid support, wherein the drug isselected from the group consisting of indomethacin, ketoprofen,celcoxib, rofecoxib, meclofenamic acid, fenoprofen, diflunisal,tolfenamic acid, naproxen, ibuprofen, flurbiprofen and nabumetone, andb. a device for providing the condensation aerosol, wherein thecondensation aerosol is formed by heating the thin layer to produce avapor of the drug, and condensing the vapor to form a condensationaerosol characterized by less than 10% drug degradation products byweight, and an MMAD of less than 5 microns.
 11. The kit according toclaim 10, wherein the device comprises: a. a flow through enclosurecontaining the solid support, b. a power source that can be activated toheat the solid support, and c. at least one portal through which air canbe drawn by inhalation, wherein activation of the power source iseffective to produce a vapor of the drug, and drawing air through theenclosure is effective to condense the vapor to form the condensationaerosol.
 12. The kit according to claim 11, wherein the heat for heatingthe solid support is generated by an exothermic chemical reaction. 13.The kit according to claim 12, wherein the exothermic chemical reactionis oxidation of combustible materials.
 14. The kit according to claim11, wherein the heat for heating the solid support is generated bypassage of current through an electrical resistance element.
 15. The kitaccording to claim 11, wherein the solid support has a surface areadimensioned to accommodate a therapeutic dose of the drug.
 16. The kitaccording to claim 10, wherein peak plasma drug concentration is reachedin less than 0.1 hours.
 17. The kit according to claim 10, furtherincluding instructions for use.
 18. The method according to claim 1,wherein the condensation aerosol is characterized by an MMAD of 0.1 to 5microns.
 19. The method according to claim 1, wherein the condensationaerosol is characterized by an MMAD of about 0.2 to 3 microns.
 20. Themethod according to claim 9, wherein the drug is indomethacin.
 21. Themethod according to claim 9, wherein the drug is ketoprofen.
 22. Themethod according to claim 9, wherein the drug is celcoxib.
 23. Themethod according to claim 9, wherein the drug is rofecoxib.
 24. Themethod according to claim 9, wherein the drug is meclofenamic acid. 25.The method according to claim 9, wherein the drug is fenoprofen.
 26. Themethod according to claim 9, wherein the drug is diflunisal.
 27. Themethod according to claim 9, wherein the drug is tolfenamic acid. 28.The method according to claim 9, wherein the drug is naproxen.
 29. Themethod according to claim 9, wherein the drug is ibuprofen.
 30. Themethod according to claim 9, wherein the drug is flurbiprofen.
 31. Themethod according to claim 9, wherein the drug is nabumetone.
 32. The kitaccording to claim 10, wherein the condensation aerosol is characterizedby an MMAD of less than 3 microns.
 33. The kit according to claim 10wherein the condensation aerosol is characterized by an MMAD of 0.1 to 5microns.
 34. The kit according to claim 32, wherein the condensationaerosol is characterized by an MMAiD of about 0.2 to 3 microns.
 35. Thekit according to claim 10, wherein the drug is indomethacin.
 36. The kitaccording to claim 10, wherein the drug is ketoprofen.
 37. The kitaccording to claim 10, wherein the drug is celcoxib.
 38. The kitaccording to claim 10, wherein the drug is rofecoxib.
 39. The kitaccording to claim 10, wherein the drug is meclofenamic acid.
 40. Thekit according to claim 10, wherein the drug is fenoprofen.
 41. The kitaccording to claim 10, wherein the drug is diflunisal.
 42. The kitaccording to claim 10, wherein the drug is tolfenamic acid.
 43. The kitaccording to claim 10, wherein the drug is naproxen.
 44. The kitaccording to claim 10, wherein the drug is ibuprofen.
 45. The kitaccording to claim 10, wherein the drug is flurbiprofen.
 46. The kitaccording to claim 10, wherein the drug is nabumetone.
 47. The kitaccording to claim 11, wherein the solid support has a surface to massratio of greater than 1 cm² per gram.
 48. The kit according to claim 11,wherein the solid support has a surface to volume ratio of greater than100 per meter.
 49. The kit according to claim 11, wherein the solidsupport is a metal foil.
 50. The kit according to claim 49, wherein themetal foil has a thickness of less than 0.25 mm.